Germ line mutation of the von Hippel-Lindau (VT-IL) tumor suppressor gene causes a hereditary cancer syndrome characterized by blood vessel tumors (hemangioblastomas) of the central nervous system and retina, renal cell carcinomas, and pheochromocytomas. Somatic VHL inactivation is common in sporadic renal cell carcinomas and hemangioblastomas. The VFIL gene product, pVHL, forms a multimeric complex that contains elongin B, elongin C, Cu12, and Rbx1. This complex is an E3 ubiquitin ligase in which pVHL targets specific proteins for degradation by the proteasome. The best understood targets are HIF1a and HIF2a, two related transcription factors that regulate hypoxia-inducible genes such as VEGF. In normal cells HIF1a and HIF2a are rapidly degraded in the presence of oxygen and only become stable when cells are made hypoxic. In cells lacking pVHL these proteins can not be degraded and accumulate to high levels leading to activation of HIF target genes. How pVFIL is prevented from degrading HIF under hypoxic conditions is not known and is the subject of specific aim 1. Specific aim 2 asks to what degree the set of pVHL-regulated genes and hypoxia-regulated genes overlap and specific aim 3 asks whether inhibition of HIF function is necessary and/or sufficient for tumor suppression by pVHL. Identification of additional proteins that bind to, and are regulated by, pVHL is the goal of specific aim 4.